Immune mechanisms are known to control the pathogenesis of atherosclerosis. However, the exact role of DCs, which are essential for priming of immune responses, remains elusive. We have shown here that the DC-derived chemokine CCL17 is present in advanced human and mouse atherosclerosis and that CCL17 + DCs accumulate in atherosclerotic lesions. In atherosclerosis-prone mice, Ccl17 deficiency entailed a reduction of atherosclerosis, which was dependent on Tregs. Expression of CCL17 by DCs limited the expansion of Tregs by restricting their maintenance and precipitated atherosclerosis in a mechanism conferred by T cells. Conversely, a blocking antibody specific for CCL17 expanded Tregs and reduced atheroprogression. Our data identify DC-derived CCL17 as a central regulator of Treg homeostasis, implicate DCs and their effector functions in atherogenesis, and suggest that CCL17 might be a target for vascular therapy.

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Regulatory myeloid immune cells, such as myeloid-derived suppressor cells (MDSCs), populate inflamed or cancer tissue and block immune cell effector functions. Lack of mechanistic insight 54 into MDSC suppressive activity and a marker for their identification hampered attempts to 55 overcome T cell-inhibition and unleash anti-cancer immunity. Here we report that human MDSCs 56 were characterized by strongly reduced metabolism and conferred this compromised metabolic 57 state to CD8 + T cells thereby paralyzing their effector functions. We identified accumulation of the dicarbonyl-radical methylglyoxal, generated by semicarbazide-sensitive amine oxidase (SSAO), to cause the metabolic phenotype of MDSCs and MDSC-mediated paralysis of CD8 + T cells. In a murine cancer model, neutralization of dicarbonyl-activity overcame MDSC-mediated T cell-suppression and together with checkpoint inhibition improved efficacy of cancer immune therapy. Our results identify the dicarbonyl methylglyoxal as marker metabolite for MDSCs that mediates T cell paralysis and can serve as target to improve cancer immune therapy. Results 92 Dormant metabolic phenotype in MDSCs 93Suppressive myeloid cells arise during chronic inflammation in tissues 17 , and tissue stromal cells 94 induce transition of monocytes into monocytic MDSCs 16 . We exploited this capacity of stromal cells to convert human peripheral blood monocytes into MDSCs, which are phenotypically similar 96 to CD14 + HLA-DR -/low suppressive myeloid cells directly isolated from cancer patients 16 , to characterize the mechanism of MDSC-mediated T cell suppression. Transcriptome analysis showed less than 200 differentially expressed genes between MDSCs and monocytes, which did not include surface molecules suitable for phenotypic discrimination or known immune suppressive mediators to explain their suppressive activity (supplementary table I-IV, Extended Data Fig. 1). Consistently, blockade of known immune suppressive mediators did not prevent MDSC-mediated T cell suppression (Extended Data Fig. 2). Surprisingly, we found downregulation of genes encoding glycolysis-related enzymes in MDSCs (Fig. 1a, and Extended Data Table V).Indeed, MDSCs showed reduced glucose uptake and Glut1 surface expression (Fig. 1b), the main transporter mediating glucose uptake in immune cells. As predicted from gene expression analysis, hexokinase activity was lower in MDSCs (Fig. 1c). To validate these results, we isolated CD14 + HLA-DR -/lo cells from tumor tissue of patients with hepatocellular carcinoma by enzymatic digestion followed by density centrifugation and flow cytometric cell sorting. We confirmed reduced glucose uptake and hexokinase activity in CD14 + HLA-DR -/low cells isolated from tumor tissue of cancer patients (Fig. 1d,e, and Extended Data Table VI), which are considered to represent MDSCs. Strikingly, MDSCs failed to utilize glucose for glycolysis and also showed reduced cellular bioenergetics, i.e. lower mitochondrial membrane potential quantified by the potentiometric mitochondrial ...